Method of relieving spasmodic conditions and pharmaceutical composition useful therefor



United States Patent "ice 3,265,577 METHGD 0F RELIEVING SPASMODIC CONDI- TIONS AND PHARMACEUTICAL CGMPOSITION USEFUL THEREFOR Tennis Kralt, Hendrik Durk 'Moed, and Willem Johannes Asma, all of Van Houtenlaan, Weesp, Netherlands, and Adolf Lindner, Vienna, Austria, assignors to North American Philips Company, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 6, 1965, Ser. No. 493,568 Claims priority, application Netherlands, Nov. 23, 1957, 222,701; Apr. 13, 1957, 216,318 12 Claims. (Cl. 167-65) The instant application is a continuation-impart of applicants co pending application Serial No. 280,784 filed May 16, 1963, which application is a continuation-inpart of application Serial No. 773,763 filed November 13, 1958, and now abandoned, and application Serial No. 802,677 filed March 30, 1959, now abandoned; said Serial No. 802,677 being \a continuation-in-part of application Serial No. 727,394, filed April 9, 1958, and now abandoned.

The instant invention relates to a new and novel method of relieving spasmodic conditions in the human being and to a novel pharmaceutical composition useful there- 01.

In the treatment of spasmodic conditions occurring because of functional or organic disorders, it has long been an object of medical research to provide a method that would affect only the target areas and have little or no side efiect. Particularly in the treatment of gastrointestinal spasms, a method which would effectively reduce the spasms yet have little or no side effects is highly desirable.

However, until now, such drugs that were available have displayed certain undesired side eifects. Thus, many of [these drugs show atropine-like side efiects resulting in dried mouth, blurred vision, inhibition of salivary secretion and retention or secretion of gastric acid.

Further, other drugs of the papaverine type which have been employed frequently, cause complete paralysis of normal peristaltic activity.

A principal object therefore, is to provide a method of relieving spastic conditions of the colon in human beings while inducing little or no side-effects.

This and other objects of our invention will be evident from the description that follows:

According to our invention, we have found that the administration of the compound 4-[N-ethyl-1"-methyl- 2"-(4"'- methoxy-phenyl) ethylalmino] butyl-3,4 dimethoxy benzoate, called hereinafter mebeverine, its non-toxic pharmaceutically acceptable acid addition salts, particularly in the form of its hydrochloride provides a particular useful method of reducing such spasms in human beings thereby eliminating or materially reducing the intensity of the associated pain. Other pharmaceutically acceptable salts such as the phosphate, bro mide, acetate, tartrate and benzoate may also be employed.

Thus mebeverine is particularly useful for the treatment of primary (essential) irritable colon syndrome i.e. spastic colitis and secondary irritable colon syndrome. Among fihe secondary colon irritable syndromes that may be treated are those due to gall bladder affections such as lbilliary dyskinesia and gall stones, diverticulosis, diverticulotis coli enteritis regionalis, enteritis, dysentery, ulcus ventriculi, duodenal ulcer, and diseases of the urinary tract such as renal calculi.

In cases of spasms which are accompanied by pain of high intensity such as those due to gall stones or renal calculi, an analgesic drug such as dipyrone Novalgin Patented August 9, 1966 (e) (sodium 1 pheny1-2,3-dimethyl-5-pyrazolone 4- methylaminomethaneculfionate), phenyl butazone or meperedine hydrochloride Demeral hydrochloride should be included withthe mebeverine.

In all cases, a sedative such as phenobarbital or a tranquilizer such as fluphenazine hydrochloride Prolixin, lprochloroperazine Oompazine, maprobamate and IChlOIOdIQZGPOXidG hydrochloride Librium may also be included.

The daily dosage of mebeverine is for an adult 200-400 mg., for a child (1-12 years) 50-250 mg. and for an infant up to 12 months less than 50 mg. Equivalent amounts of its non-toxic acid addition salts may be used.

The mebeverine may be administered orally in tablet or liquid form, by suppositories or parenterally by intramuscular injection.

The tablets and suppositories each contain from 20 to mg. of mebeverine. The ampules for injection contain from 10 to 50 mg. of mebeverine per The syrup contains from 4 to 20 mg. of mebeverine per cc.

The mebeverine may be prepared according to the method disclosed in our pending United States patent application Serial No. 280,784, filed May 16, 1963, of which the instant case is a continuation-in-part.

Our invention will now be described with greater detail with references to the following examples:

Examples of suitable pharmaceutical formulations of mebeverine are as follows.

I. Coated tabletsa. Kernel V Mg./tab1et Mebeverine hydrochloride 50 Lactose 10 Polyvinyl Pyrrolidone 0.5 Formaldehyde-caseine 4.5 Carboxymethylcelluliose 4 Magnesium stearate 1 b. Coating:

Talc 15 Sugar (crystal) 54.5 Starch (potato) 0.5 Carnauba wax 0.02

Shellac wax 0.02 Dammar resin 0.03

II. Ampules Mebeverin HCl 50 Benzyl alcohol 15 Distd. water ad lml.

III. Suppository- Mebeverine 100 Tert. calcium phosphate 350 Sugar (powdered) 350 Starch (corn) 350 Talc 40 Magnesium stearate 10 Massupol 400 Massupol: See Merck Index, 7th ed., p. 638.

The mebeverine HCl tert. calcium phosphate, sugar and starch are sieved (40 mesh), moistened with ethanol/water (SO/50). The mass is granulated, dried 5 hours at 50 C. and mixed with the tale and magnesiumstearate. From this mixture tablets are fiormed and coated at 40 C. with the molten massupol.

3 4 IV. Coated tablets: Mebeverine-t-Novalgine 1 (Noval- Each coated tablet contains 50 mg. mebeverine hydrogin) or sodiumnovaminesulfonatechloride.

a Kernel, Mg nablet Each ampule contains 100 mg. mebeverine hydrochlo- Mebeverme 50 n sodiumnovaminesufonate 250 5 Each p (composltlum) contains 3gof Powdered Sugar 50 mebeverine hydrochloride and 2.5 -g. of Novalgm. Starch (potato) 25 Example Gelatin 2 Formaldehyde-caseine 4 tablet (50 mg. of mebeverine hydrochloride in each Talc 33 10 tablet) were administered three times a day to 6 infants Magnesium stearate 33 Of 4-6 Weeks for a period ofthree weeks. All of these Distd. Water, :1 liter/ 100,000 tablets. infants were sufiering from aerophagy or meteorism. In Ethanol 96% v./v. (denat.), :1 liter/ three cases, a pronounced mitigation of the colic attack 100,000 bl t was achieved. In the other three cases, the colic attacks b ceased only during the administration of the mebeverine 98 1 hydrochloride.

Ta c 367'7 While we have described our invention in connection 2 (crysta 3 5 with specific embodiments and applications, other modifications thereof will be readily apparent to those skilled i 7'75 9 in this art without departing from the spirit and scope of ltamu'm dloxl e the invention as defined in the appended claims. Shellac wax 0.12 Wh t 1 Carnauba wax 0.12 a We 6 mm Dammar resin O 2 1. A method of treating spastic conditions of the colon "T in a human comprising administering to said human a ggg tetrachlonde 1/ IOOOOOO member selected from the group consisting of the base 4' [N ethyl 1" methyl 2" (4' methoxy phen- Dlstd' Water :10 1/ 100900 tablets yl) ethylamino] butyl 3,4 dimethoxy benzoate and 1\N l di It of l-fen l-2,3-d'meth lrazo- 1One g a u z acid 1 y Dy istasltgion toxic pharmaceutlcally acceptable acid addit on Ampules 'i' 2. A method of treating spastic conditions of the colon Meheverme 20 in a human comprising orally administering to said husqdlumnovammesufonate 500 man a member selected from the group consisting of the Dlstd- Water: ad 1 base 4' [N ethyl-l"-met-hyl-2"-(4'-methoxy-phenyl)- VL suppository mebeVerine+NOva1gine ethylamino]-butyl-3,4-dimethoxy benzoate and its non- Meb v rj l-lcl 100 toxic pharmaceutically acceptable acid addition salts.

sodium o a i es lfo at 1000 A method of treating spastic conditions of the colon Vehicle x 2150 in a human comprising parenterally administering to said xv hi 1 ltml re area from Veretable oils human a member selected from the group consisting of e M eftin g iioint 36-7 0. 40 the base 4'-[N-ethyl-l"-methyl-2"-(4"-methoxy-phenyl)- g fi q g p h ethylamino]-butyl-3,4-dimethoxy benzoate and its non- 1.1;,Z ?f3 toxic pharmaceutically acceptable acid addition salts. Acid value: 0.5 4. .The method of claim 1 wherein the hydrochloride VII. Coated tablets mebeverine+phenobarbitalsalt 18 p y K l; Mgjtabl t 5. The method of claim 1 wherein 200-400 mg. of

Mebeverine.HCl 50.0 t e ba e or an equivalent amount of the salt is admin- Phenobarbit-al 10,0 istered daily to a human adult.

Polyvinylpyrrolidone 0.5 6- The method of claim 1 wherein -250 mg. of the Formaldehyde-caseine 4,5 base or the equivalent amount of the salt is administered Carboxymethylcellulose MZ 851 4.0 50 daily to a human bemg- Magnesium stearate 1.0 7- The method of claim 1 wherein up to 50 mg. of the Etha l b (d :45 li /1 000,- base or an equivalent amount of the salt is administered 000 tablets. daily to a human infant.

8. A method of treating spastic conditions of the colon b Coatm S 1 1 in a human comprising administering to said human a as Xamp 6 member selected from the group consisting of the base Illustrative examples employing mebeverine are shown 4' [N ethyl 1" methyl 2" (4' methoxy phenin the following table and examples: yl) ethylamino] butyl 3,4 dimethoxy benzoate and TABLE Age in Duration of Undeslrable Case No. years Sex Diagnosis Daily dose treatment Eficct side efiects in days 1R.E 68 m Spastic eolitis 6c0ated tablets- 36 Excellent None. 2B.G.B 13 m Gastric spasms 2coated tablets 11 d0 Do. 3F.A 55 m Gastroduolocated tablets- 26 Good Do.

denitis, eirrhosis of liver. 4R.F 25 f Polyserositis, 1ampule(com- 1 Excellent Do.

colic pains in positium). abdomen. 5V.G 34 r Adnexitis do 1 Slight Do. 6F.M 63 f Hepatic colic, 3 ampules (com- 2 Excellent-. Do.

cholecystitis positium) with lithiasis. '7T.F 63 m Neoplastic- Zampules 9 Good Do.

schalasia of the oesophagus.

its non-toxic pharmaceutically acceptable acid addition salts together with an analgesic drug.

9. A method of treating spastic conditions of the colon in a human Comprising administering to said human 21 member selected from the group consisting of the base 4 [N ethyl 1" methyl 2" (4" methoxy-phenyl) ethylarnino] butyl 3,4 dimethoxy benzoate and its non-toxic pharmaceutically acceptable acid addition salts together with dipyrone.

10. An antispasmodic composition particularly adapted for treating spastic conditions in colons in humans comprising in an antispasmodically efiected amount, a member selected from the group consisting of the base 4'-[N- ethyl 1" methyl 2" (4"' methoxy-phenyl) ethyl amino]-butyl-3,4-dimethoxy benzoate and the pharmaceuti-cally acceptable acid addition salts thereof and a major amount of a pharmaceutical carrier therefor.

11. An antispasmodic composition particularly adapted for treating spastic conditions of the colon in humans comprising in an antispasmodically elfective amount, 4-

[N ethyl 1" methyl 2" (4"' methoXy-phenyl)- ethylamino]-butyl-3,4-dimethoxy benzoate hydrochloride, and a major amount of a pharmaceutical carrier therefor.

12. An antispasmodic composition particularly adapted for treating spastic conditions of the colon in humans comprising in an antispasmodically effective amount, 4'- [N ethyl 1" methyl 2" (4"' methoxy-phenyhethylamino]-butyl-3,4-dimethoxy benzoate hydrochloride, dipyrone and a major amount of a pharmaceutical carrier therefor.

No references cited.

JULIAN S. LEVITT, Primary Examiner.

MARTIN I. COHEN, Assistant Examiner. 

1. A METHOD OF TREATING SPASTIC CONDITIONS OF THE COLON IN A HUMAN COMPRISING ADMINISTERING TO SAID HUMAN A MEMBER SELECTED FROM THE GROUP CONSISTING OF THE BASE 4'' -(N - ETHYL - 1" - METHYL - 2" - (4"'' - METHOXY - PHENYL) - ETHYLAMINO) - BUTYL - 3,4, - DIMETHOXY BENZOATE AND ITS NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS. 